Collaborating investigators at the University of Massachusetts medical Center and Yale University School of Medicine have jointly developed a Program Project on hematopoietic stem cell growth and differentiation. The research themes focus on genetic characterization of the hematopoietic stem cell phenotype and the relationship of cell cycle phase to stem cell phenotypic properties with an emphasis on in vivo engraftment in a myeloablated mouse model. These themes coalesce in efforts to improve the transfer of genes in vitro in novel vectors to hematopoietic stem cells and, in turn, in studies designed to improve engraftment of gene-carrying stem cells. This Program Project is organized into a team approach for the integrated pursuit of 5 projects, 2 research support cores and an administrative core. The individual projects address the identification of critical genes in primitive stem cells and genes as well as transcription factors defining decisions between renewal, cell cycle progression and differentiation; the engraftment potential of hematopoietic stem cells as it relates to cell cycle status and cytokine stimulation; and, the development of novel anti-HIV vectors for integration into both proliferating and non-proliferating stem cells to manipulate proliferative status and to enhance engraftment. Two core laboratories support molecular genetics and stem cell purification. The stem cell purification core is a particularly critical link between Yale and UMMC. This Program Project application brings together investigators from two institutions, from many departments and divisions with a wide variety of both basic and clinical research expertise to address basis problems in stem cell biology an to create a viable base for the development of clinical gene therapy.